Method and compositions for the production of chlorine dioxide

ABSTRACT

The present invention relates to a method for producing chlorine dioxide (ClO 2 ) disinfecting solution which preferably minimizes the amount of residual chlorite ion (ClO 2  -) so that the disinfecting solution can be used in a number of industries, preferably including the food, food processing, drinking water, pharmaceutical production, medical and dental industries. Chlorine dioxide generating solutions which are substantially corrosion free as well as gel formulations are also disclosed.

RELATED APPLICATIONS

This application is a continuation-in-part application of U.S. patentapplication serial No. 08/093,529, entitled "Method for the Productionof Chlorine Dioxide", filed Jul. 19, 1993, which is acontinuation-in-part application of U.S. patent application serial No.07/846,468, entitled "Method for the Production of Chlorine Dioxide",filed Mar. 4, 1992, now abandoned, and a continuation-in-partapplication of U.S. patent application serial No. 07/980,262, entitled"Chlorine Dioxide Generation Method in Low Acidity Compositions", filedNov. 23, 1992, now abandoned.

FIELD OF THE INVENTION

The present invention relates to a method for maximizing the productionof chlorine dioxide (ClO₂) disinfecting solution which method alsopreferably minimizes the amount of residual chlorite ion (ClO₂ ⁻).Preferably, the disinfecting solution can be used in a number of relatedindustries, including the food, food processing, drinking water,pharmaceutical production, medical and dental related industries.

In a related embodiment, the present invention also relates to a methodfor the generation of chlorine dioxide (ClO₂) in low aciditydisinfecting compositions (i.e., having an initial pH between about 3.5and about 4.5-5.0) which is suitable for applications where corrosion, apH related property, is a concern and is required to be either preventedor minimized so that the disinfecting composition can be used in thetreatment of metal-containing substrates such as dental and medicalinstruments and devices.

A further embodiment relates to chlorine dioxide generating formulationsin gel form for the topical administration of chlorine dioxide to theepidermis, i.e., skin of animals and humans. In the gel formulationsaccording to the present invention, in order to maximize chlorinedioxide production for purposes of disinfecting the skin or producing anintended pharmacological effect, an initial pH (which initial pH may bethe result of the inclusion of an acid and an aqueous soluble salt ofchlorite, or optionally, a hydroxyl-free aldehyde disproportionationagent--which addition to the acid and chlorite salt generally does notaffect the pH of the solution) of about 3.0 to about 4.5 is used. ThispH range is consistent with the safe and effective topical delivery ofgel formulations according to the present invention.

BACKGROUND OF THE INVENTION

Chlorine dioxide, an indirect food additive, has been found to beespecially useful as a disinfectant, antiseptic and sanitizer. It iswidely used to disinfect drinking water and various water supplies. Inaddition, chlorine dioxide finds use as a bleaching agent for flour,fats, textiles and as an antiseptic. In addition, chlorine dioxideexhibits great benefit as a disinfectant, for example, an antimicrobial,for treating a number of skin conditions of mammals, including humans.

Although it has great beneficial chararacteristics, chlorine dioxide cannot be transported commercially as a concentrated gas for its use andinstead has been generated at the site where it is used.

Chlorine dioxide has shown great utility as an antiseptic for treatingmetal substrates such as dental and medical instruments and devices.However, the prior art methods for generating chlorine dioxide sufferfrom the disadvantage that large quantities of chlorite remain as aresidue. Chlorite residues on food handling equipment and medical anddental surfaces that are to come in contact with humans are to beavoided or substantially minimized according to FDA and EPA regulations.In addition, in topical chlorine dioxide generating formulations, thelarge chlorite residues which remain using the prior art methods is aproblem because of the tendency of the formulations to produce anirritation and allergic responses.

Separately, chlorine dioxide exhibits certain corrosive properties whichare believed to be pH related, especially low pH related. Thus, incertain applications, it is beneficial to generate chlorine dioxide at apH which would avoid or minimize corrosion during the disinfectingprocess.

The production of ClO₂ solutions is well known in the art. The generalprior art procedure has been to mix sodium chlorite (NaClO₂) with anacid. As a rule, the stronger the acid, the faster and more efficientwill be the production of chlorine dioxide. The general formula for theproduction of chlorine dioxide using sodium bisulfate is as follows:##STR1##

According to the reaction, the hydrogen ion concentration produced ismuch greater using a relatively strong acid, as opposed to a weaker acid(having a lower pKa). This increased hydrogen ion concentration willproduce optimal concentrations of chlorous acid. Thus, lowerconcentrations of strong acids are needed to generate the sameconcentration of chlorous acid as are produced using weaker acids.

The prior art methods for generating chlorine dioxide result in largeresidues of chlorite ion. This can be a disadvantage where one wishes tominimize the residual chlorite ion, especially when disinfecting orcleaning sensitive machinery or equipment. Thus, when the prior artsolution is evaporated from the surface of food equipment, for example,the chlorite ion either in protonated form or as the conjugate base(depending upon pH) remains as unwanted residue.

Another requirement in the food handling and related industries is theneed for raw materials or ingredients which are safe to handle in thepreparation of the disinfectant. Strong acids such as nitric orhydrochloric may be dangerous to the unskilled personnel in the foodhandling unit and inappropriate for generating chlorine dioxide in thiscase. The requirement is for the inclusion of reagents which are safe touse and, after generating chlorine dioxide, produce side products whichare non-toxic and/or biodegradable.

Gel formulations which produce chlorine dioxide for topical delivery areknown in the art. These prior art formulations however, suffer fromcertain limitations. For one, these formulations produce only limitedconcentrations of chlorine dioxide. Second, these formulations are notefficient and residual chlorite is a problem. High concentrations ofresidual chlorite are believed to be at least partially responsible foruntoward irritation and allergic responses which have characterized theprior art gel compositions. Other components of the prior art gelformulations which remain include organic acids, which, within thedesired pH range for topical delivery, are primarily in the form of thefree acid. The free acid form of the organic acids of the prior artcompositions tends to more readily penetrate the skin than does theanionic counter ion of the acid. Consequently, the use of high pKaorganic acids such as are used in prior art gel formulations tend toexacerbate skin irritation problems and should be avoided.

Although a number of attempts have been made in the art to enhance theefficiency of chlorine dioxide production and minimize the amount ofresidual chlorite ion, the results have generally been unimpressive. Todate, there has been no report of the use of a hydroxyl free aldehyde toenhance the production of chlorine dioxide from an acid and a salt ofchlorite at a pH of less than about 5.0.

OBJECTS OF THE PRESENT INVENTION

It is an object of the present invention to provide a method forproducing chlorine dioxide for use on food equipment and relatedsurfaces including dental and medical surfaces.

It is another object of the present invention to preferably minimize theamount of residual chlorite salt in the final chlorine dioxide solutionand ultimately, where applicable, on the treated surface.

It is an additional object of the present invention to provide a methodfor producing chlorine dioxide utilizing materials which are safe tohandle.

It is a further object of the present invention to generate chlorinedioxide from chlorite ion and minimally toxic or non-toxic(substantially non-toxic) chlorine dioxide generators which yieldsubstantially non-toxic and/or biodegradable side products from thegeneration of chlorine dioxide.

It is still an additional object of the present invention to provide amethod for generating chlorine dioxide which enhances the production ofchlorine dioxide while minimizing the residual chlorite ion.

It is yet another object of the present invention to generate chlorinedioxide from chlorite ion in a liquid or gel composition utilizingnon-toxic low pKa acids.

It is yet a further object of the present invention to provide achlorine dioxide generation method in a liquid composition containing arelatively low concentration of acid which may be used as a disinfectanthaving essentially no corrosive properties.

It is still a further object according to the present invention toprovide chlorine dioxide generating compositions in gel form for topicaldelivery to the epidermis of animals or the skin of humans. Thesechlorine dioxide gel formulations of the present invention are capableof delivering high concentrations of chlorine dioxide safely to atopical site to be used as a skin disinfectant or to treat a number ofconditions of the skin, including microbial and fungal infections, amongothers.

These and other objects of the present invention may be readily gleanedfrom the description of the invention which follows.

DESCRIPTION OF THE FIGURES

FIG. 1 is a diagrammatic representation of a system for producingchlorine dioxide from a salt of a chlorite and an acid, preferably abiologically compatible acid and optionally, a disproportionation agent.The reaction(s) to form chlorine dioxide occurs in the reaction chamber(C). It is noted that the pipes, chambers and vats as set forth in FIG.1 are generally made of high density polyethylene and/or polypropylene.

FIGS. 2A and 2B are diagrammatic representations of a two-part systemcomprising two containers, one for chlorite salt and the other for theacid. In FIGS. 2A and B, the two parts could be considered as twoseparate containers, with or without dispensing pumps. A measuring cupcan be used for removing approximately equal volumes of the chloritepart and the acid part.

DETAILED DESCRIPTION OF THE INVENTION

The term "salt of a chlorite" or "chlorite salt" is used throughout thespecification to describe a salt of chlorite which is readily soluble inan aqueous system and which readily dissociates into chlorite anion andcounterion (generally, metal). Two particularly preferred salts ofchlorites for use in the present invention include sodium chlorite andpotassium chlorite.

The term "acid" is used throughout the specification to describe proticacids, i.e., acids that release hydrogen ions in solution. Acids for usein the present invention include strong inorganic acids such ashydrochloric, sulfuric, sulfamic and nitric acid, preferably as diluteacid, organic acids such as citric, fumaric, glycolic, lactic, malic,and tartaric acid, among others, and preferred acids such as sodium andpotassium bisulfate (NaHSO₄ and KHSO₄), phosphoric acid and maleic acid.

The term "low pKa acid", "non-toxic low pKa acid" "biologicallycompatible low pKa acid" is used throughout the specification todescribe acids which are relatively strong (have pKa's of about 2.1 orlower, preferably below about 1.94, the pKa of chlorous acid so as toshift the equilibrium to chlorous acid generation) and are easily orrelatively safely handled, are generally compatible with biologicalsystems (they are substantially non-toxic) and are non-caustic. Low pKaacids donate a large fraction of hydrogen ions by favoring the reactionwhich consumes hydrogen ions and generates chlorine dioxide. By virtueof the low pKa, the acids utilized in the present invention are highlyionized and smaller quantities of the low pKa acid would be needed toprotonate chlorite ions to form chlorous acid compared to higher pKaacids. Consequently, the acids have low residual levels and the mixtureis easily raised in pH when touching skin or disinfecting an instrument.

In non-corrosive and gel formulation aspects according to the presentinvention, the use of a low pKa acid within a range of pH of about 3.0to about 4.0-4.5 in combination with a salt of chlorite and ahydroxyl-free aldehyde is preferred and is consistent with thesubstantial absence of the free acid form of the low pKa acid insolution. The substantial absence of the free acid form is consistentwith compositions which exhibit little, if any, corrosivecharacteristics and produce little, if any, irritation of the skin.

The residues that are formed from these biologically compatible acidsare generally the sodium and/or potassium salts of the acids, suchresidues being safe, non-corrosive and acceptable as either direct orindirect food and/or pharmaceutical additives. Examples of biologicallycompatible or non-toxic acids for use in the present invention includesodium and potassium bisulfate (NaHSO₄ and KHSO₄), phosphoric acid,sulfamic acid and maleic acid. The bisulfates have pKa's of about1.9-2.0, phosphoric acid has a pKa of about 2.15 and maleic acid has apKa of about 1.94. Other biologically compatible acids which may be usedin the present invention include phosphoric acid,ethylenediaminetetraacetic acid (EDTA, as the free acid or themonosodium salt), among others.

For purposes of the present invention, hydrochloric, nitric andconcentrated sulfuric acid or sulfuric acid in its free acid form mayalso be used in the present invention, but their use is generallylimited compared to the biologically compatible acids. In certainembodiments according to the present invention, these acids arepreferably used in diluted form.

The term "chlorous acid disproportionation agent", "disproportionationagent" or "aldehyde agent" is used throughout the specification todescribe a number of disproportionation agents which enhance the rate ofdisproportionation of chlorous acid to significantly increase the amountof chlorine dioxide which is produced and minimize residual chloriteion. The disproportionation agents according to the present inventionare chosen for their ability to substantially enhance the rate andefficiency (yield) at which chlorine dioxide is formed from chlorousacid (even at relatively high pH's and low concentrations of acid- aconsideration in the embodiments which minimize corrosion), for theirability to form their biologically compatible substantially non-toxicorganic acid side products and for their ability to minimize residualchlorite ion. Thus, by using a disproportionation agent according to thepresent invention, one can produce effective quantities of ClO₂,minimize the amount of acid used and raise the pH of the ClO₂-generating solution to a non-corrosive level, if desired.

Disproportionation agents for use in the present invention preferablyinclude hydroxyl free aldehydes, most preferably, substantiallynon-toxic hydroxyl free aldehydes such as acetaldehyde, benzaldehyde,glutaraldehyde, cinnamic aldehyde, propionaldehyde, paraldehyde and2-Furfural (bran oil), among others.

Preferred disproportionation agents for use in the present inventioninclude those aldehydes that are substantially non-toxic themselves andwhich are converted during the disproprotionation process tosubstantially non-toxic side products. The hydroxyl free aldehydesacetaldehyde, benzaldehyde, glutaraldehyde and propionaldehyde areparticularly preferred for use in the present invention. Hydroxyl freealdehyde compounds are preferred over hydroxyl containing aldehydecompounds for use in the present invention, because of the tendency ofthe hydroxyl containing aldehydes to undergo condensation in solutionsat low pH, which decreases the rate of formation of chlorine dioxide.

The term "hydroxyl free aldehyde" is used throughout the specificationto describe the preferred disproportionation agents for use in thepresent invention. Hydroxyl free aldehydes are those chemical compoundscontaining an aldehyde moiety which is free of hydroxyl groups. Whilenot being limited by way of theory, it has quite unexpectedly beendiscovered that the inclusion of a hydroxyl free aldehyde in combinationwith an acid and a salt of chlorite (at a pH of less than about 5.0,more preferably less than about 4.5) will maximize the production ofchlorine dioxide and minimize the residual chlorite compared with theprior art methods, especially including those methods which use vicinalhydroxyl containing hemi-acetal compounds such as aldoses and othersugars.

The term "corrosive properties" is used throughout the specification todescribe properties such as those producing corrosion on metalsubstrates such as medical and/or dental devices. These properties arederived from factors such as excess residual acidity (low pH) and/orexcess residual chlorite ion.

The term "enhanced chlorous acid disproportionation" is used throughoutthe specification to describe the production of chlorine dioxide fromchlorous acid in the presence of a hydroxyl free aldehydedisproproportionation agent, a combination which has a faster rate andgreater efficiency of chlorite ion use even when the pH is less acidicand which generally produces chlorine dioxide in greater amounts and athigher concentrations than without a disproportionation agent. This isan unexpected result. In general, in the absence of a disproportionationagent, the amount of chlorine dioxide which is generated in a reactionat a pH of about 3.9 during a 15 minute period is generally no greaterthan about 1-2 parts per million. This indicates that the rate ofconversion of chlorous acid to chlorine dioxide in this case is veryslow and the yields are low. In addition, residual acid remains, thusincreasing the potential for producing corrosion.

Utilizing a disproportionation agent in the form of a hydroxyl freealdehyde at the same starting pH of 3.9, the concentration of chlorinedioxide generated in a period of about ten minutes or less may be asmuch as about 40 ppm or more. In this case, hydrogen ions and residualchlorite ions are consumed by the disproportionation of chlorous acid,such that at the end of a 15 minute period, the pH rises to about 4.3.In certain cases the concentration of chlorine dioxide generated may beas much as 100 ppm or more. This more efficient process for producingchlorine dioxide results in chlorite ion levels being substantiallyreduced relative to processes which generate chlorine dioxide in theabsence of a hydroxyl free aldehyde. In preferred embodiments accordingto the present invention, at the end of the 15-minute period, theresidual chlorite ion levels are about 60% or less of the initialchlorite ion.

In the present invention, it has surprisingly been found that theinclusion of a hydroxyl-free aldehyde disproprotionation agent incombination with an acid and a salt of chlorite in a first aqueoussolution will generate within a period of about ten minutes at leastabout two times, preferably at least about 4 times and as much as ten ormore times the concentration of chlorine dioxide generated in a secondsolution containing the same concentration and type of acid and salt ofchlorite, but including an aldose as disproportionation agent at thesame concentration that the aldehyde was used in the first solution.This is a particularly surprising result inasmuch as the prior art (U.S.Pat. No. 4,986,990 to Davidson, et al.) teaches that the inclusion ofdisproportionation agents at an acidic pH should be in the form of avicinal hydroxyl containing composition.

The terms "minimize residual chlorite ion", "minimizing residualchlorite ion" or "substantially reduce residual chlorite ion" are usedthroughout the specification to describe reactions to produce chlorinedioxide which preferably yield no more than about 85% by weight residualchlorite ion (based upon the initial weight of chlorite used). Morepreferably, the amount of residual chlorite ion is less than about 70%by weight and most preferably the amount of residual chlorite ion isless than about 60% by weight. In certain instances, the amount ofresidual chlorite ion may be considerably less than about 30% by weight.

The term "substantially non-toxic" is used throughout the specificationto describe disproportionation agents and/or biologically compatibleacids which are used to generate chlorine dioxide in the method(s)according to the present invention. Substantially non-toxic means thatthe materials are safely handled and are generally compatible withbiological systems in amounts used to generate chlorine dioxide relativeto compositions which are considered "substantially toxic." The term"substantially" is used to describe the non-toxic acids anddisproportionation agents for use in the present invention because ofthe fact that almost all substances, including water, may become toxicto a biological system in certain amounts.

The term "substantial quantity" is used to describe amounts of chlorinedioxide which are produced using the method according to the presentinvention and are believed to be useful. A substantial quantity ofchlorine dioxide for purposes of the present invention is at least about1 part per million, because chlorine dioxide is a disinfectant at thatconcentration and higher concentrations. In the present invention,chlorine dioxide is preferably produced in a concentration of at leastabout 5 parts per million, most preferably in a concentration of atleast about 20-40 parts per million. Concentrations of chlorine inexcess of 100 parts per million are readily available using the presentinvention.

The terms "low acidity composition" and "high pH acid composition" areused throughout the disclosure to describe a chlorine dioxide-generatingcomposition (producing at least about 1 ppm chlorine dioxide) and havinga relatively low concentration of acid to produce an initial pH of about3.5 to about 4.5-5.0, and which comprises an amount of a water solublesalt of chlorite with an amount of an acid, preferably a low pKa acid,effective to produce a pH within the above range. The composition may bedry or in solution.

The term "chlorite part" is used throughout the specification todescribe the form in which an amount of a water soluble salt of chloriteeither in dry or liquid state is added to the acid part.

The term "acid part" is used throughout the specification to describethe form in which an amount of a water soluble low pKa acid either indry or liquid state is added to the chlorite part.

The term "low acidity condition" is used throughout the specification todescribe the condition at which at least 1 part per million (ppm) ofchlorine dioxide is generated in a solution with a starting pH rangingfrom about 3.5 to about 4.5-5.0. This condition is provided by combiningan effective amount of a low pKa acid with an amount of a water solublesalt of chlorite.

The overall pH range for purposes of the present invention is from lessthan about 2.0 to about 5.0, most preferably about 2.0 to about 4.5. Inthe case of topical gel formulations, the pH ranges from slightly lessthan about 3.0 to about 5.0 (i.e., compatible with topical delivery toan animal or human or no less than about pH 2.5), preferably about 3.0to about 4.5. In the case of non-corrosive or "low acidity" solutionsfor use in disinfecting medical and dental instruments, the pH rangesfrom about 3.5 to about 4.5-5.0.

The term "effective amount" is used throughout the specification todescribe a minimum amount, quantity or concentration of a component,i.e., an acid (preferably, a low pKa acid), disproportionation agent orchlorite ion included to generate an intended effect, i.e., aconcentration of chlorine dioxide. The term effective amount when usedto describe the acid, preferably a low pKa acid, is used to describethat amount of acid, either in dry or liquid form which, when combinedwith chlorite in solution, will generate a desired concentration ofchlorine dioxide, i.e., at least about 1 part per million (ppm) andpreferably at least about 5 ppm of chlorine dioxide from chlorous acid.By definition, 1 part per million is equal to 0.0001% by weight.

The term "gel composition" or "gel" is used to describe an aqueouscomposition according to the instant invention which includes an amountof a gelling agent effective for gelling the composition. Gelcompositions are preferred for topically delivering chlorine dioxide toa site in need of disinfection or chlorine dioxide therapy. In general,the amount of a gelling agent included in the aqueous chlorine dioxidegenerating compositions according to the present invention ranges fromabout 0.5% to about 5-6% (or more) by weight of the composition, with apreferred amount of gelling agent falling within the range of about 1%to about 4% by weight.

Gelling agents for use in the present invention include, for example,natural and synthetic gelling agents including polysaccharides extractedfrom plants such as pectins found in green land plants and carrageenans,agars found in seaweeds, and polysaccharides extracted from legumeseeds, such as the galactomannans, including guar gum and locust bean(carob) gum. Other gelling agents include high molecular weightpolyoxyalkylene crosslinked acrylic polymers as well as the highlypreferred cellulosics such as hydroxymethyl cellulose, hydroxypropylcellulose, hydroxyethyl cellulose, among others including high molcuelarweight polyethylene glycols, polyvinyl alcohol-boric acid gels,polyacrylamide gels and crosslinked polyvinylpyrrolidones, among others.The gelling agents according to the present invention are sterilizedprior to inclusion in the instant formulations. It is preferred that thegelling agent should be stable to pH's ranging from less than about 2 togreater than about 10 so that they can be used in all formulations(including Parts A and B which are mixed to generate chlorine dioxide).

The present invention relates to a method of producing chlorine dioxidecomprising:

1) combining an amount of a salt of chlorite with an amount of an acid,preferably a low pKa biologically compatible acid effective to produce asubstantial quantity of chlorous acid; and

2) providing an amount of a disproportionation agent in the form of ahydroxyl free aldehyde chemical compound effective to enhance chlorousacid disproportionation to chlorine dioxide, the initial pH of thecomposition containing the salt of chlorite, the acid and aldehydecompound being less than about 5.0.

This method unexpectedly enhances the rate and amount of chlorinedioxide produced and reduces the amount of residual chlorite ionrelative to prior art methods and is preferably compatible with food,medical device and dental surfaces. This method may be performed at aninitial pH no greater than about 5.0 and preferably within a pH range ofabout 2 to about 4.5. In the case of gel compositions, the initial pHpreferably ranges from about 3.0 to about 4.5. Where corrosionresistance is not desired, a pH of less than about 2.5 is preferred,because high concentrations of chlorine dioxide may be generated andresidual chlorite concentrations are quite low (in certaincircumstances, less than about 10-30%). In certain embodiments accordingto the present invention, substantial corrosion resistance is instilledby utilizing an initial pH of about 3.5 to about 4.5 in combination withan inorganic acid.

The present invention also relates to a method of producing chlorinedioxide comprising:

1) combining an amount of a salt of chlorite with an amount of an acid,preferably a low pKa biologically compatible acid, effective to producea substantial quantity of chlorous acid; and

2) providing an amount of a disproportionation agent in the form of anon-toxic hydroxyl free aldehyde chemical compound effective to enhancechlorous acid disproportionation to chlorine dioxide, said aldehydeafter disproportionation giving rise to a substantially non-toxicorganic acid and/or organic acid salt side product.

In a preferred method according to the present invention which providessubstantial corrosion resistance, lower concentrations of acid,preferably a low pKa inorganic acid and chlorite are used at a pHranging from about 3.5 to about 5.0, preferably about 3.5 to about 4.5compared to prior art methods, further diminishing the residual chloriteion. Gel formulations according to the present invention make use of apH ranging from about 3.0 to about 4.5. It is noted that the initial pHof the formulation is that pH generated when acid and chlorite salt arecombined. However, the initial pH described above is also applicable tocompositions or formulations which include a hydroxyl-free aldehyde, thealdehyde being a neutral species which does not appreciably alter orotherwise change the initial pH of the formulations which contain acidand chlorite salt.

It has been discovered unexpectedly that the inclusion of a low pKainorganic acid in combination with chlorite and a hydroxyl free aldehydeat an initial pH of about 3.5 to about 5.0, preferably about 3.5 toabout 4.5 to produce chlorine dioxide will reduce corrosion of metalsubstrates. While not being limited by way of theory, the choice of alow pKa inorganic acid is believed to be preferred to minimize corrosionbecause of the tendency of the low pKa acid to be ionized within the pHrange of about 3.5 to 5.0, thus minimizing the free acid form of theacid, and consequently, the corrosion.

In the first method according to the present invention, an effectiveamount of a salt of a chlorite, preferably sodium or potassium chloriteis combined with a biologically compatible acid to produce a substantialquantity of chlorous acid. In a second step, the chlorous acid producedis allowed to disproportionate to form chlorine dioxide. Chlorinedioxide pursuant to the present invention may be generated in astep-wise manner, or alternatively, may be generated from the acid,chlorite salt and aldehyde being combined at the same time.

In the method according to the present invention, preferred salts ofchlorites include sodium and potassium chorite. The preferred acids arelow pKa acids according to the present invention which are generallyconsidered safe, user friendly and substantially non-toxic, for examplesalts of bisulfate, sulfamic acid, maleic acid, phosphoric acid andethylenediaminetetraacetic acid (EDTA, as the free acid or themonosodium salt), among others. It is noted that numerous additionalacids may be used in the present invention to generate chlorine dioxideincluding numerous organic acids, for example, citric, propionic,fumaric, glycolic, lactic, malic, tartaric and acetic, among others andinorganic acids such as sulfuric, sulfamic, hydrochloric and nitric(preferably, in a dilute concentration). Generally, the concentration ofchlorite salt used to generate chlorous acid in the present inventionrepresents at least about 0.0005M and preferably ranges from about0.002M to about 0.5M or slightly higher. In the embodiments which aresubstantially non-corrosive, the amount of chlorite salt comprises atleast about 0.0005M and preferably ranges from about 0.002M to about0.2M.

The amount of acid, preferably biologically compatible acid, added tothe chlorite salt is generally that amount effective to provide aninitial pH of the reaction mixture (which mixture includes acid andchlorite salt or preferably, acid, chlorite salt and aldehyde, amongother components) below about 5.0, preferably below about 4.5 and morepreferably lower than about 3.5 or less. In embodiments according to thepresent invention where corrosion resistance is not consideredimportant, preferably, as a rule of thumb, the low pKa acid is added inan amount which will render the initial pH in the reaction chamber,i.e., in the presence of chlorite ion and aldehyde, to a level belowabout 2.5 and most preferably to a level at or below about 2.2. Inembodiments according to the present invention in which the corrosionresistance is desired, the initial pH generally ranges from about 3.5 toabout 5.0, preferably about 3.5 to about 4.5. In gel formulationsaccording to the present invention, the initial pH of the formulationwhich includes acid, chlorite salt and optionally, aldehyde ranges fromabout 3.0 to about 4.5.

The acid is generally provided in a concentration of about 0.00005M toupwards of about 1M, depending upon the final pH of the solutiondesired. In corrosion resistant compositions, the concentration of acidpreferably ranges from about 0.01M to about 0.2M, depending upon theamount of chlorite in the composition. In compositions in which havingthe characteristic of corrosion resistance is not important, the amountof acid preferably ranges from about 0.01M to upwards of 1M or more.These concentrations will usually provide a pH of less than about 2.5and usually less than about 2.0. A low pH value is generally associatedwith a greater rate and production of chlorine dioxide. Concentrationsof acid producing pH's above or below these values (up to a pH of about5.0) may also be used, depending upon the amount of chlorite to beconverted to chlorine dioxide, as well as the pH desired in the reactionchamber and the ultimate concentration of chlorine dioxide desired.

In the first method according to the present invention, the chloritesalt is combined with the acid preferably at about 15° C. to about 30°C. to produce chlorous acid. Thereafter, the chlorous acid is left todisproportionate to chlorine dioxide. In general, the disproportionationstep is carried out in the same aqueous medium where the formation ofchlorous acid occurs. The temperature of the disproportionation step mayvary, but will generally range from about 15° C. to about 30° C. orhigher. After production, the chlorine dioxide solution may be useddirectly or diluted depending upon the desired or intended use.

In a second method according to the present invention, the use of adisproportionation agent, preferably in the form of a hydroxyl freealdehyde chemical composition, will enhance and hasten the production ofchlorine dioxide from chlorous acid. In this aspect of the presentinvention, either before, during or after the formation of chlorousacid, an effective amount of an agent for disproportionating chlorousacid to chlorine dioxide is added to the solution. While thedisproportionation agent may be added after the formation of chlorousacid, preferably the disproportionation agent is already present in theacid solution when the acid solution is combined with the aqueousmixture of chlorite salt. The inclusion of the aldehydedisproprotionation agent does not appreciably affect the pH of theinitial solution which includes acid and chlorite salt, because thealdehyde is a neutral species. By combining the aldehydedisproprotionation agent initially with acid and chlorite salt in thisway, as soon as chlorous acid is generated, the disproportionationreaction may be enhanced. The overall result will be to shift theequilibrium toward more chlorous acid generation and consequently, morechlorine dioxide formation. Using a disproportionation agent, at least10% and generally at least about 30-40% up to about 80% or higher ofchlorite ion is converted to chlorine dioxide and chloride ion. In theabsence of a disproportionation agent such as a hydroxyl free aldehydedisproportionation agent, the conversion is significantly slower and isless efficient (often, significantly less than about 2% of the initialchlorite ion is converted to chlorine dioxide and/or chloride). Thesignificant enhancement of chlorine dioxide production and thelimitation in residual chlorite ion using a hydroxyl free aldehydedisproportionation agent is an unexpected result.

It is noted that in this aspect of the present invention which utilizesa hydroxyl free aldehyde disproportionation agent to enhance chlorousacid disproportionation to form chlorine dioxide and minimize residualchlorite, any acid which produces an initial pH in the reaction mixtureof about 5.0, preferably 4.5 or lower may be utilized, but preferably alow pKa biologically compatible acid is used. In this regard, thefollowing acids, among other are useful: salts of bisulfate, maleicacid, sulfamic acid, phosphoric acid and ethylenediaminetetraacetic acid(EDTA, as the free acid or the monosodium salt), are most preferred.Numerous additional acids may also be used in the present invention togenerate chlorine dioxide including a variety of organic acids, forexample, citric, propionic, fumaric, glycolic, lactic, malic, tartaricand acetic, among others and inorganic acids such as sulfuric,hydrochloric and nitric (preferably, in a dilute concentration), amongothers.

In one aspect of the present invention, a gel matrix is described. Thegel matrix according to the present invention is intended for use onmammalian skin, preferably human skin, as a delivery vehicle forchlorine dioxide in disinfecting amounts. In the present invention, theuse of certain chemical components which produce chlorine dioxideaccording to the instant invention are particularly useful in a gelmatrix for delivering chlorine dioxide.

The present invention which relates to a topical gel formulationpreferably utilizes a low pKa acid selected from the group consisting ofan aqueous soluble bisulfate salt, maleic acid, phosphoric acid,ethylenediaminetetracetic acid, monosodium ethylenediaminetetraceticacid and mixtures thereof and an aqueous soluble salt of chlorite incombination with an aldehyde disproportionation agent selected from thegroup consisting of acetaldehyde, benzaldehyde, propionaldehyde,glutaraldehyde and 2-furfural at an initial pH ranging from about 3.0 toabout 4.5. This combination of additives in aqueous solution is combinedwith a gelling agent, the gelling agent being included in an amounteffective to produce a gel for topical delivery of the formulation. Thiscombination of ingredients as disclosed herein at an initial pH of about3.0 to about 4.5 is consistent with the rapid formation and delivery ofhigh concentrations of chlorine dioxide (i.e. at least about 10 ppm,preferably at least about 25 ppm and most preferably at least about 50ppm or more for topical applications of chlorine dioxide). In manyinstances the production of 100 or more ppm of chlorine dioxide isreadily attainable. This is not easily attained by the gel formulationsof the prior art. While acids other than low pKa acids may be used, thelow pKa acids are clearly preferred for use in the present gelformulations.

Compared to the prior art methods, the gel compositions according to thepresent invention produce concentrations of chlorine dioxide within aperiod of no greater than about ten minutes in amounts of at least two,preferably at least five and most preferably ten or more times theconcentration of chlorine dioxide produced from virtually identicalchlorine dioxide generating compositions wherein an aldose of the priorart is substituted for the hydroxyl-free aldehyde disproportionationagent of the present invention in the same molar concentration.

It is surprising that high concentrations of chlorine dioxide can beproduced in a gel matrix at a relatively high pH consistent with thetopical delivery of chlorine dioxide. In addition, the gel compositionsaccording to the present invention, because of the highly efficientproduction of chlorine dioxide at the desired pH, produce highconcentrations of chlorine dioxide which are advantageous for treatingnumerous topical conditions, yet leave a reduced amount of chloriteresidue compared to prior art methods. The reduced amount of chloriteresidue is advantageous in topical applications according to the presentinvention because the reduced residue will significantly reduce thelikelihood that an animal or person being exposed to the topicalformulation will develop an allergic reaction or skin irritation to thechlorite. The use of biologically compatible low pKa acids is clearlypreferred in the present invention because of the tendency of thesecompositions to limit the irritancy of the formulations on the skin. Inaddition, the low pKa acids tend to have little buffering capabilitycompared with organic acids, and consequently, their use will allow theskin to easily adjust to a suitable pH, thereby producing lessirritation of the skin.

The preferred gel formulations according to the present invention areadvantageous compared to certain prior art formulations. By utiliizingthe biologically compatible low pKa acids according to the presentinvention as described above, the present gel formulations minimize theexposure of the skin to acid in its free acid form. For example,inorganic acids, due to the strength of their conjugate bases relativeto that of chlorite ion tend to give up the proton (H+) in favor ofchlorous acid production (equilibrium favors chlorous acid production,not the formation of acid). In producing chlorine dioxide in gelformulations according to the present invention, the low pKa acids willprimarily exist in their counter ion form, not their free acid form.While not being limited by way of theory, it is believed that thecounter ion form of the acid, compared to the free acid form, is a lessirritating moiety and creates a formulation which is less reactive andirritating to the skin. On the other hand, gel formulations which relyon the inclusion of organic acids with higher pKa's to generate chlorinedioxide at a pH ranging from about 3.0 to about 4.5 will need to havemore organic acid added to establish the initial pH and will also havemore acid in the free acid form during the period the gel is exposed tothe skin. The result of these less preferred formulations, is to producea gel which is more irritating than the gels of the present invention.

In the gel formulations according to the present invention, compared toprior art methods which may include the use of an aldose or diol as adisproportionation agent, the present invention produces chlorinedioxide at a much faster rate and in a more efficient manner. Forexample, the gel formulations according to the present invention producea concentration of chlorine dioxide within about ten minutes of at leastabout two times, preferably at least about four times and in many cases,as much as ten or more times the chlorine dioxide generated from thevirtually identical compositions where an aldose has been substitutedfor the hydroxyl-free aldehyde disproprotionation agent. This is anunexpected result.

The gel formulations according to the present invention include, inaddition to acid, chlorite salt, hydroxyl-free aldehyde and water, anamount of a gelling agent effective to gel the formulation for topicaldelivery on the skin of an animal or human. The amount of gelling agentranges from about 0.5% to about 6.0% by weight with a preferred range ofabout 1% to about 4% by weight. Unlike in an aqueous system, a gelformulation utilizes thickening agents which, when dispersed in aqueoussystem, produce a viscous format. This viscous format may slightlyimpair the formation and mobility of chlorine dioxide as this formatimpairs the ability of the individual reactants to produce chlorinedioxide and the formed chlorine dioxide to come in contact with thetarget area of the skin. Thus, the inclusion of the particularcomponents which are used in the gel formulations according to thepresent invention are adapted to produce high concentrations of chlorinedioxide.

In addition to effective amounts of acid, chlorite salt, hydroxyl-freealdehyde disproportionation agent, water and gelling agent the gelformulations according to the present invention advantageously employnumerous additives which are commonly used in cosmetic andpharmaceutical formulations. These additives include, for example,surfactants such as sodium lauryl sulfate and poloxamer™(polyoxypropylene/polyoxyethylene block copolymer), among numerousothers, emulsifiers, emollients, such as lanolin and glycerolmonostearate, among others, appropriate wound healing agents, lubricantsand film-formers such as dimethicone, vaseline and mineral oil, amongothers, and diluents and fillers such as ethyl alcohol and isopropylalcohol and humectants such as glycerin and propylene glycol. Theseadditives are generally included in amounts ranging from about 0.025% toabout 8% by weight or more. Fragrances are also advantageously employedin amounts ranging from about 0.01% to about 1% by weight or more. Skinpenetrants, such as D-limonene, among numerous others, may also beemployed to quickly dissolve the active ingredients and enhance theeffect of topically administered chlorine dioxide by enhancing theirskin penetration.

In general, the amount of hydroxyl-free disproportionation agent used inthe present invention is an effective amount which varies depending uponthe amount of chlorite ion and acid used and the desired concentrationof chlorine dioxide to be generated. In general, the amount ofdisproportionation agent used in the present invention ranges from about10 parts per million to about 20,000 parts per million or more (about0.001% to about 2.0% by weight of the chlorine dioxide generatingsolution). In general, on a mole to mole basis, the amount ofdisproportionation agent utilized varies from about 1/10 to about 1/2the amount of chlorite used, and preferably about 1/3 to about 1/2.While it is possible to utilize a disproportionation agent inconcentrations above and below this amount, it is noted that atconcentrations of disproportionation agent substantially below 1/10 themolar concentration of chlorite, the rate at which disproportionation ofchlorous acid to chlorine dioxide occurs may be diminished. At molarconcentrations of disproportionation agent significantly above about 1/2the concentration of chlorite, residual amounts of disproportionationagent may remain in solution which could result in instability in theresulting chlorine dioxide solution. The effective amount ofdisproportionation agent is chosen to maximize chlorine dioxideformation and minimize the amount of residual chlorite in the chlorinedioxide mixture at a particular concentration of the initial salt ofchlorite and at the desired initial pH.

In the general method according to the present invention, the apparatusas set forth in FIGS. 1 and 2A and 2B are representative of systemswhich may be used to generate chlorine dioxide. As set forth in FIG. 1,a chosen amount of chlorite salt is dissolved in water in vat A.Preferably, the chlorite salt is the sodium or potassium salt. Theconcentration of chlorite salt chosen is an effective amount whichgenerally ranges from about 0.001 to about 0.5 Molar (generally, forexample, about 0.09 g. to about 45 g./liter of sodium chlorite, butamounts above and below these concentrations may also be used in certainembodiments). The chlorite salt is first added to water and dissolved.Depending upon the type and final concentration of chlorite chosen, thepH of the solution in Vat A may range from about 9.0 to significantlyabove about 10. A pH above 10, for example about 10.5, is oftenemployed.

A second solution, contained in Vat B, is prepared containing aneffective amount of an acid, preferably a biologically compatible acid,for example, sodium bisulfate. In embodiments according to the presentinvention in which corrosion is not a concern, the pH of the solutionwithout a disproportionation agent is preferably maintained below about2.5. The amount of acid chosen is that amount which is effective toproduce a substantial quantity of chlorous acid. This amount of acidwill generally provide an initial pH of the reaction mixture (whichincludes the chlorite salt) in which chlorine dioxide is produced belowabout pH 2.5. Optionally, into this acid solution, an effective amountof a hydroxyl free aldehyde disproportionation agent may be added toenhance disproportionation of chlorous acid to chlorine dioxide.Generally, the inclusion of the hydroxyl-free aldehyde will notappreciably affect the pH of the resulting solution. The final pH of theacid solution which includes the disproportionation agent in this aspectof the invention is generally less than about 5 and is preferably lessthan about 2.5. The pH of this solution is chosen to produce an initialpH in the reaction mixture of less than about 5.0. In this aspect of thepresent invention which includes a hydroxyl-free aldehydedisproportionation agent, any acid may be used including any of theaforementioned acids, among others, but preferably a low pKabiologically compatible acid such as salts of bisulfate, maleic acid,sulfamic acid, phosphoric acid and ethylenediaminetetraacetic acid(EDTA, as the free acid or the monosodium salt) is used.

Vats A and B are each stoppered so that the contents of each vat may bemetered into reaction chamber C. Each or both of the Vats may begraduated. The stoppering of vats A and B (valves (1) and (2)) willallow a measured or pre-measured amount of the contents of each Vat tobe delivered in a controllable manner to the reaction chamber C whilevalve (3) is open and (4) is closed. In the reaction chamber, thechlorite is acidified with the low pKa biologically compatible acid toproduce chlorous acid and subsequently, the generated chlorous acid isdisproportionated in situ into chlorine dioxide. The concentration ofchlorine dioxide increases within the reaction chamber until such timeas the reaction is completed. In general, the reaction(s) to producechlorine dioxide without the aid of the disproportionation agent is slowand may require about 30 minutes or higher to be completed (level off).

With an effective amount of a hydroxyl free aldehyde disproportionationagent, the concentration of chlorine dioxide generated within a periodof about 10 minutes ranges from at least about 1 ppm and preferably atleast about 5 ppm to upwards of 100 ppm or more. More preferably, thecompositions according to the present invention produce concentrationsof chlorine dioxide in an amount of at least about 25 ppm within aperiod of no greater than about 10 minutes. The amount of chlorinedioxide produced in a period of about 10 minutes using the combinationof an acid, an aqueous soluble salt of chlorite and a hydroxyl-freealdehyde according to the instant invention is generally at least abouttwo times, preferably at least about 4 times and as much as about tentimes or more the production of chlorine dioxide using the same type andconcentration of acid and salt of chlorite, but substituting an aldosefor the hydroxyl-free aldehydes of the instant invention. This is aparticularly surprising result when the prior art and in particular,Davidson, et al., in U.S. Pat. No. 4,986,990, teach the inclusion of avicinal hydroxyl containing disproportionation agent at an acidic pH,i.e., below a pH of about 5.

In the gel formulations according to the present invention whichutilize, the amount of chlorine dioxide generated is generally at leastabout 5 parts per million, more preferably at least about 25 parts permillion and most preferably at least about 50 ppm within a period ofabout ten minutes. The amount and rate of chlorine dioxide produced inthe gel formulations according to the present invention is generally atleast about two times, preferably at least about 4 times and as much asten times or more the production of chlorine dioxide compared to a gelcomposition which uses the same type and concentration of acid and saltof chlorite, but where an aldose is substituted for the hydroxyl-freealdehyde disproportionation agent.

The unexpectedly high concentrations of chlorine dioxide which aregenerated within a short period of time (about 15 minutes or less) bythe compositions according to the present invention are particularlyuseful in topical applications for treating a wide variety of conditionsof the skin including herpes, acne, dandruff, poison ivy, diabeticulcers, bed sores, warts and nail fungus. In addition, compositionsaccording to the present invention may be used to treat sunburn andsuperficial wounds of the skin. In general, when treating these abnormalconditions of the skin, a concentration of chlorine dioxide ranging fromabout 10 ppm to about 100 ppm or more is applied to the skin conditionat least once a day and up to four or more times a day. In preferredembodiments according to the present invention, a gel composition whichproduces a concentration of at least about 25 ppm up to about 100 ppm isadministered or applied to the topical condition to be treated. In manyinstances, at least some instantaneous relief from the symptoms of thetopical condition is seen within the first half hour upon application ofthe gel to the skin to be treated. For further treatment and theelimination of the skin condition, longer periods of treatment areadvised, e.g., from one day up to several weeks or longer. Fortherapeutic treatment, the application of the gel composition accordingto the present invention to the condition to be treated at least once aday and up to eight or more times per day is generally advised. One ofordinary skill in the art will be able to readily adjust theconcentration of chlorine dioxide administered as well as the durationand frequency of application in order to treat the patient in the mostefficacious manner.

A particularly useful application of the gel compositions according tothe present invention includes the treatment of the inflammatory affectsof bug bites. It has unexpectedly been discovered that the topicalapplication of concentrations of chlorine dioxide of at least about 10ppm and more preferably at least about 25 ppm on skin which is inflamedor otherwise affected by bug bites (urticaria, rash, hives, etc.) willalleviate the symptomotology and reduce the inflammation of the skinaffected by the insect bite. This is an unexpected result. In thistreatment method, compositions which produce concentrations of at leastabout 10 ppm chlorine dioxide and preferably at least about 25 ppmchlorine dioxide within a period no greater than about 15 minutes areparticularly useful in treating skin affected by bug bites.

The production of chlorine dioxide may be monitored photometrically at360 nm using an extinction coefficient of 1250 M⁻¹ cm⁻¹ as described onpp. 244-245 of "Chemistry of Chlorine Dioxide", In Progress in InorganicChemistry, Vol. 15 , S. J. Lippard (Editor), Wiley-Interscience, NewYork (1972). In certain aspects according to the present invention, thefinal concentration of chlorine dioxide is preferably greater than about20 ppm, and more preferably the final concentration of chlorine dioxidein the reaction chamber ranges from about 80-100 parts per million (ppm)to upwards of 400 ppm or more. The concentration of chlorine dioxidewhich is produced using higher pKa acids, especially organic acids athigher pH values, will generally fall within the same range set forthabove. Generally, on a mole to mole basis, the amount of chlorinedioxide produced using an organic acid will be lower than the chlorinedioxide concentration produced from a low pKa acid.

After the completion of the formation of chlorine dioxide in reactionchamber C, the contents of reaction chamber C are deposited intodilution tank D by opening valve 4 (valve 5 is closed). Here, thechlorine dioxide solution from reaction chamber C is mixed with water orother aqueous solution in dilution tank D (generally about a 20-40 folddilution, preferably about 30 fold) so as to create a chlorine dioxidesolution with a final concentration generally ranging from slightly lessthan about 1 ppm to about 10 ppm, with a preferred concentration ofabout 1 ppm to about 5 ppm. The pH of the final diluted solution ofchlorine dioxide for use as a disinfectant preferably ranges from about4.5 to about 7 with a more preferred range from about 5.5 to about 6.5.

In FIGS. 2A and 2B, which figures are representative of thenon-corrosive aspect of the instant invention, the chlorite part rangesfrom about 50 ppm to about 50,000 ppm. The pH of the chlorite part maygenerally range from about 9.0 to about 10.8 although an initial pHoutside of this range may also be used. The acid part contains aneffective amount of an acid, preferably a low pKa acid which is morepreferably non-toxic and the pH of the acid part ranges from about 3.5to about 4.5. Into the acid part, optionally, may be added an amount ofan aldehyde disproportionation agent effective to enhancedisproportionation of chlorous acid to chlorine dioxide. The amount ofaldehyde disproportionation agent ranges from about 20 ppm to about40,000 ppm. In this aspect of the present invention in which thealdehyde disproportionation agent is utilized, any acid may be usedincluding any of the aforementioned acids, among others, but preferablya non-toxic low pKa acid is used. When the chlorite part is added to theacid part (which preferably contains the hydroxyl free aldehyde), thecombined mixture has a pH of less than about 5.0.

The final solutions of chlorine dioxide in diluted form may be used forpurposes of disinfecting surfaces, especially surfaces which may requirereduced amounts of chlorite ion, for example, food equipment, andmedical devices and dental equipment. In addition, the solutionsaccording to the present invention may also be used for any other knownpurpose especially including drinking water. The number of applicationsof the chlorine dioxide solutions according to the present invention isbelieved to be larger than for solutions which are produced according toprior art methods because the solutions of the instant invention arecompatible with food, medical and dental equipment as well as other usesknown in the art.

EXAMPLES

The following examples are provided to illustrate the present inventionand should not be construed to limit the scope of the invention of thepresent application in any way.

Example 1

To Vat A (See FIG. 1) was added an aqueous solution containing about 0.7g./liter of pure sodium chlorite (T.R.-AMC Chemicals, a Division ofTR-Metro Chemicals, Inc., Ridgefield, N.J.). To Vat B was added about0.4 g./liter of potassium bisulfate, which produced a pH of about 1.9.To this solution about 0.2 g/liter of acetaldehyde was added.

The contents of Vat A and Vat B were emptied into the reaction chamber Cby opening valves 1, 2 and 3 (valve 4 is closed). The pH of the mixturein the reaction chamber is approximately 2.2. The reaction mixture wasallowed to stand for a period of ten minutes after which timeapproximately 92% of the initial chlorite salt had been converted tochlorine dioxide (40%) and chloride ion (60%). The concentration ofchlorine dioxide in the aqueous solution in the reaction chamber wasabout 110 ppm as measured spectrophotometrically at 360 nm using anextinction coefficent of 1250 M⁻¹ cm⁻¹. The concentration of chloriteion which remains was approximately 30 ppm. The concentrated chlorinedioxide solution is thereafter delivered to the dilution tank D anddiluted 30 fold to a final concentration of 3.5 ppm chlorine dioxide anda pH of about 6. In the final diluted disinfectant solution, theconcentration of chlorite ion is about 1 or less ppm. The relativelyhigh pH of the solution is caused by the 30-fold dilution, theproduction of water using up hydronium (H₃ O⁺) ions during the reactionand the effect of chlorine dioxide as a Lewis Acid is minimized at highdilution.

Example 2

Same method employed as in example 1, except that into Vat B was added0.4 g/liter of potassium bisulfate in combination with 0.18g/liter ofpropionaldehyde. The resulting solution produced a concentration ofchlorine dioxide of about 110 ppm in the reaction chamber C as measuredspectrophotometrically at 360 nm using an extinction coefficent of 1250M⁻¹ cm⁻¹. A 30 fold dilution of the final concentration of chlorinedioxide produced a final concentration in the dilution chamber D ofabout 3.5 ppm chlorine dioxide and a final concentration of chlorite ionof about 1 or less ppm.

Example 3

Same method employed as in example 1, except that into Vat B was added0.4 g/liter of potassium bisulfate in combination with about 0.29g/liter of benzaldehyde. The resulting solution produced a concentrationof chlorine dioxide of about 30-40 ppm in the reaction chamber C asmeasured spectrophotometrically at 360 nm using an extinction coefficentof 1250 M⁻¹ cm⁻¹. A 30 fold dilution of the final concentration ofchlorine dioxide produced a final concentration in the dilution chamberD of about 1.0 ppm chlorine dioxide and a final concentration ofchlorite ion which is significantly less than if disproportionation hadnot been included.

Example 4

In an embodiment related to the non-corrosive aspect according to thepresent invention, as in Example 1, the following two-part formulationwhen combined in about a 1:1 ratio provides a composition useful for thedisinfection of hard substrates such as dental and/or medical devices.

    ______________________________________                                        Liquid Disinfectant                                                                            Percent by Weight                                            ______________________________________                                        Chlorite Part                                                                 Sodium chlorite (80%)                                                                            0.250%                                                     EDTA, tetra sodium (98%)                                                                         0.095%                                                     Sodium lauryl sulfate                                                                            0.004%                                                     Deionized Water    q.s.                                                       Acid Part                                                                     Potassium bisulfate (anhydrous)                                                                  0.400%                                                     Sodium propionate  0.150%                                                     Glutaraldehyde (50%)                                                                             0.080%                                                     Cinnamic aldehyde  0.015%                                                     Deionized Water    q.s.                                                       ______________________________________                                    

As noted, the disproportionation agent in the form of a hydroxyl freealdehyde chemical compound, namely glutaraldehyde, is preferably addedto the acid part. In this example, cinnamic aldehyde is used as afragrance. The resulting composition after 15 minutes has a pH of about4.2 and produces a concentration of chlorine dioxide of about 45 ppm asmeasured spectrophotometrically at 360 nm (molar absorptivity of 1250per mole/centimeter). Within this period, about 40% of the initialchlorite is consumed. This composition is readily applicable fordisinfection of hard surfaces such as dental and/or medical devices.

Example 5

In a preferred composition related to the non-corrosive aspect of thepresent invention, which results from about a 1:1 ratio of a combinationof the following two part formulation, a liquid disinfectant is obtainedwhich is useful for applications on dental and/or medical devices.

    ______________________________________                                        Liquid Disinfectant                                                                            Percent by Weight                                            ______________________________________                                        Chlorite Part                                                                 Sodium chlorite (80%)                                                                            0.250%                                                     EDTA, tetra sodium (98%)                                                                         0.095%                                                     Sodium lauryl sulfate                                                                            0.004%                                                     Deionized Water    q.s.                                                       Acid Part                                                                     Potassium bisulfate (anhydrous)                                                                  0.360%                                                     Sodium propionate  0.150%                                                     Propionaldehyde    0.010%                                                     Deionized Water    q.s.                                                       ______________________________________                                    

As noted, the disproportionation agent in the form of a hydroxyl freealdehyde chemical compound, namely propionaldehyde, is preferably addedto the acid part. The resulting composition has a pH of about 3.9 andproduces a concentration of chlorine dioxide of about 38 ppm as measuredspectrophotometrically at 360 nm (molar absorptivity of 1250 permole/centimeter during a period of about 10 minutes. Within this period,about 15 % of the initial chlorite is consumed. This composition isreadily applicable for disinfection of hard surfaces such as dentaland/or medical devices.

Example 6

In yet another embodiment related to the non-corrosive aspect accordingto the present invention, the following two-part formulation, whencombined in about a 1:1 ratio, provides a composition useful for thedisinfection of hard substrates such as dental and/or medical devices.The pH of the composition is about 4.2 and produces about 27 ppm ofchlorine dioxide during an aging period of about 15 minutes.

    ______________________________________                                        Liquid Disinfectant                                                                            Percent by Weight                                            ______________________________________                                        Chlorite Part                                                                 Sodium chlorite (80%)                                                                            0.190%                                                     EDTA, tetra sodium (98%)                                                                         0.092%                                                     Sodium lauryl sulfate                                                                            0.004%                                                     Deionized Water    q.s.                                                       Acid Part                                                                     Potassium bisulfate (anhydrous)                                                                  0.300%                                                     Sodium propionate  0.150%                                                     Propionaldehyde    0.030%                                                     Deionized Water    q.s.                                                       ______________________________________                                    

Example 7 Comparison of the Present Invention At a pH Less Than About5.0 With Prior Art Methods

The present invention which utilizes an acid and a salt of chlorite incombination with a hydroxyl free aldehyde chemical compound at a pH nogreater than about 5.0 to generate chlorine dioxide was compared withthe prior methods of Hampel, as set forth in U.S. Pat. No. 2,323,594("the Hampel method") and Davidson, as set forth in U.S. Pat. No.4,986,990 ("the Davidson method"). Control experiments, which excluded adisproportionation agent, were also performed in which chlorine dioxidewas generated by mixing sodium chlorite with an acid at a pH of about2.65 and about 5. The control experiments were performed in order togenerally assess the value of the disproportionation agent in thepresent invention, the Hampel method and the Davidson method. Theresults of this comparison evidence the production of unexpectedlygreater quantities of chlorine dioxide using the method of the presentinvention compared to the prior art methods.

General Method

Chlorine dioxide was generated in the following experiments, all ofwhich were performed at room temperature under essentially identicalconditions (initial sodium chlorite and disproportionation agentconcentration). In certain experiments, the initial pH was constant; inother cases the pH was changed from one experiment to another, primarilyto determine the effect that pH had on the formation of chlorine dioxideand/or residual chlorite levels. Chlorine dioxide levels were determinedin each case by standard spectrophotometric methods, using a wavelengthof 360 nm. Sodium chlorite levels were determined by iodometrictitrations using 0.1N thiosulfate reagent. The starting pH for thevarious experiments was about 2.65 or 5.0 for the present method, theDavidson method and the control experiment, and 7.2 for the Hampelexperiment.

I. Experiments at pH 2.65

The studies performed at pH 2.65 (the present invention, the Davidsonmethod or the control experiment) utilized a first solution (part B)containing 0.140% by weight potassium bisulfate (anhydrous) in water,and in the case of the present invention and the Davidson method, a0.0091 molar concentration of a disproportionation agent in addition tothe acid. In the present invention acetaldehyde was thedisproportionation agent and in the Davidson method mannose, glucose,glycerin or inositol (as taught by Davidson) was the disproportionationagent. To initiate chlorine dioxide formation, an aqueous solutioncontaining 0.102% by weight sodium chlorite (part A) was added to theacidic solution (part B) in equal volumes and mixed.

The above experiments were also compared with the Hampel method. Usingthe Hampel method, chlorine dioxide was generated at a pH of 7.2utilizing 0.040% of acetaldehyde (0.0091 molar) in buffer solution. Thebuffer solution was prepared by dissolving 34.5 grams of sodiumphosphate monobasic (NaH2PO4.H2O) in 500 ml of deiozined water,adjusting the pH to 7.2 using a solution of sodium hydroxide and thendiluting to 1 liter with deionized water. Chlorine dioxide formation andthe pH of the solution at room temperature in each of these experimentswere measured at 2 minutes, 5 minutes and 10 minutes after initialmixing.

The results of these low pH experiments, along with the results obtainedusing the Hampel method, are presented and compared in Tables 1 and 2.Table 1 evidences a tremendous difference in the amount and rate offormation of chlorine dioxide using the present invention at pH 2.65compared with the methods of Hampel, Davidson or the control experiment.It is noteworthy that the aldose and diol disproportionation agents ofDavidson were only marginally better than the control experiment ingenerating chlorine dioxide at pH 2.65. For the Hampel method, thegeneration of chlorine dioxide was considerably less than the control.

Table 2 sets forth the concentration of chlorite remaining in solution 5minutes after initial mixing to form chlorine dioxide in the differentmethods. The results evidence that the amount of chlorite remaining insolution after 5 minutes using the present invention is about 28 toabout 35 fold less than it is for the control experiment or theexperiments using the method of Hampel or Davidson.

                  TABLE 1                                                         ______________________________________                                        PPM Level of Chlorine Dioxide Generated                                              Present                                                                Time Con-    Inven-  Davidson                                                 pH   trol    tion    Mann. Gluc. Glyc. Inos.                                                                              Hampel                            ______________________________________                                        2    2.0     150     3.8   3.0   2.0   2.0  0.2                               Min. 2.65    2.70    2.65  2.60  2.60  2.60 7.2                               pH                                                                            5    4.0     160     8.60  5.80  3.90  4.0  0.6                               Min. 2.65    2.75    2.60  2.65  2.65  2.60 7.2                               pH                                                                            10   6.0     160     12.6  8.0   6.0   5.5  1.0                               Min. 2.60    2.70    2.65  2.60  2.60  2.60 7.2                               pH                                                                            ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Percent Residual Levels of Sodium Chlorite (NaClO.sub.2)                      After 5 Minute Aging Period                                                   Experiment     pH       % NaClO.sub.2 Remaining                               ______________________________________                                        Control        2.65     96.8%                                                 Present Invention                                                                            2.65      2.75%                                                Davidson                                                                      Mannose        2.65     96%                                                   Glucose        2.65     96%                                                   Glycerin       2.65     96.8%                                                 Inositol       2.65     96.8%                                                 Hampel         7.2      76.6%                                                 ______________________________________                                    

II. Experiments at pH 5.0

The studies performed at pH 5.00 (the present invention, the Davidsonmethod or the control experiment) utilized a first solution (part B)containing 0.050% by weight potassium bisulfate (anhydrous) in water,and in the case of the present invention and the Davidson method, a0.0091 molar concentration of a disproportionation agent in addition tothe acid. In the present invention acetaldehyde was thedisproportionation agent and in the Davidson method mannose, glucose,glycerin or inositol (as taught by Davidson) was the disproportionationagent. To initiate chlorine dioxide formation, an aqueous solutioncontaining 0.102% by weight sodium chlorite (part A) was added to theacidic solution (part B) in equal volumes and mixed.

The above experiments were also compared with the Hampel method astaught above. As above, chlorine dioxide formation and the pH of thesolution at room temperature in each of these experiments were measuredat 2 minutes, 5 minutes and 10 minutes after initial mixing.

The results of these low pH experiments, along with the results obtainedusing the Hampel method, are presented and compared in Tables 3 and 4.Table 3 evidences a huge difference in the amount (at least 37 foldmore) and rate of formation of chlorine dioxide using the presentinvention at pH 5.0 compared with the methods of Hampel, Davidson or thecontrol experiment. It is noted that the aldose and dioldisproportionation agents of Davidson were slightly better than thecontrol experiment in generating chlorine dioxide at pH 5.0, butsignificantly less efficient than the hydroxyl free aldehyde used in thepresent invention. For the Hampel method, the generation of chlorinedioxide was slightly better than the control or Davidson.

Table 4 sets forth the concentration of chlorite remaining in solution 5minutes after initial mixing to form chlorine dioxide in the differentmethods. The results evidence that the amount of chlorite remaining insolution after 5 minutes using the present invention is significantlyless than it is for the control experiment or the experiments using themethod of Davidson. The amount of chlorite remaining after employing themethod of Hampel is similar to the present invention, althoughsignificantly more chlorite did remain in the case of Hampel comparedwith the present invention.

                                      TABLE 3                                     __________________________________________________________________________    PPM Level of Chlorine Dioxide Generated                                       Time               Davidson                                                   pH   Control                                                                            Present Invention                                                                      Mann.                                                                             Gluc.                                                                             Glyc.                                                                             Inos.                                                                             Hampel                                     __________________________________________________________________________    2 Min.                                                                             N.D. 15.0     ≦0.1                                                                       ≦0.1                                                                       ≦0.1                                                                       ≦0.1                                                                       0.2                                        pH   5.0  5.0      5.0 5.0 5.0 5.0 7.2                                        5 Min.                                                                             N.D. 22.0     ≦0.2                                                                       ≦0.1                                                                       ≦0.1                                                                       ≦0.1                                                                       0.6                                        pH   5.0  5.3      5.0 5.0 5.0 5.0 7.2                                        10 Min.                                                                            N.D. 37.0     ≦0.2                                                                       ≦0.1                                                                       ≦0.1                                                                       ≦0.1                                                                       1.0                                        pH   5.0  5.2      5.0 5.0 5.0 5.0 7.2                                        __________________________________________________________________________     PPM = Parts Per Million                                                       Min. = Minutes                                                                N.D. = Not Detectable                                                         Mann. = Mannose (Aldose)                                                      Gluc. = Glucose (Aldose)                                                      Glyc. = Glycerin                                                              Inos. = Inositol (Cyclic Alcohol)                                        

                  TABLE 4                                                         ______________________________________                                        Percent Residual Levels of Sodium Chlorite (NaClO.sub.2)                      After 5 Minute Aging Period                                                   Experiment     pH     % NaClO.sub.2 Remaining                                 ______________________________________                                        Control        5.00   about 100%                                              Present Invention                                                                            5.20   70.6%                                                   Davidson                                                                      Mannose        5.00   about 100%                                              Glucose        5.00   about 100%                                              Glycerin       5.00   about 100%                                              Inositol       5.00   about 100%                                              Hampel         7.2    76.6%                                                   ______________________________________                                    

Example 8 Use of Organic Acid As Substitute for Low pKa Acids

In the above-described experiments, organic acids such as acetic acid,tartaric acid, citric acid, lactic and similar organic acids aresubstituted for sodium bisulfate. The method is performed at pH 2.70 and5.0. The results indicate that at pH 2.70 the generation of chlorinedioxide (about 70 PPM) using the present invention is significantlygreater and the residual chlorite remaining (about 54%) is significantlyless than using the methods of Davidson at a pH of 2.70 or Hampel(7.20). At pH 5.0, the results of the present invention (about 20 PPMchlorine dioxide generated and about 72% residual chlorite remaining)are comparatively better than either the method of Davidson performed atpH 5.0 or the Hampel method. However, the difference between the resultsgenerated by the present invention using an organic acid at a pH of 5.0and the methods of Davidson at a pH of about 5.0 and Hampel at pH 7.2are not as great as in the case where the present method is performed atthe lower pH of 2.70. Moreover, the use of a low pKa acid such as sodiumbisulfate also produces significantly better results than using anorganic acid (higher pKa) at the same pH.

Example 9 Comparison of the Present Invention at a pH ranging from 3.5to about 4.5 With Prior Art Methods

The present invention which relates to a non-corrosive formulations,employing a vicinal hydroxyl free aldehyde in combination with a salt ofchlorite and an acid at an initial pH of about 3.5 to about 4.5, wascompared with the method described in U.S. patent application No.4,986,990 ("Davidson") and the method described in U.S. Pat. Number2,323,594 ("Hampel") as generally described above in Example 7. Inaddition to the Davidson and Hampel methods, control experiments, whichexcluded a disproportionation agent, were also performed in whichchlorine dioxide was generated by mixing sodium chlorite with an acid ata pH of about 3.5 and about 4.5.

Chlorine dioxide was generated using the present invention and theabove-referenced prior art methods in the following experiments, all ofwhich were performed at room temperature under essentially identicalconditions (initial sodium chlorite and except for the controlexperiment, disproportionation agent concentration). In all cases theinitial pH was constant (at about 3.5 or 4.5 or, in the case of theHampel method, about 7.2). Chlorine dioxide levels were determined foreach experiment by standard spectrophotometric methods, using awavelength of 360 nm. Sodium chlorite levels were determined byiodometric titrations using 0.1N thiosulfate reagent. The starting pHfor the various experiments was about 3.5 or 4.5 for the present method,the Davidson method and the control experiment, and 7.2 for the Hampelexperiment (as taught by Hampel).

The experiments performed at an initial pH of about 3.5 and 4.5 (thepresent invention, the Davidson method or the control experiment)utilized a first solution (part B) containing about 0.050% by weightpotassium bisulfate (anhydrous) in water, and in the case of the presentinvention and the Davidson method, a 0.0091 molar concentration of adisproportionation agent in addition to the acid (as in Example 7). Inthe present invention, acetaldehyde was the disproportionation agent andin the Davidson method mannose, glucose, glycerin or inositol (as taughtby Davidson) was the disproportionation agent. To initiate chlorinedioxide formation, an aqueous solution containing about 0.10% by weightsodium chlorite (part A) was added to the acidic solution (part B) inequal volumes and mixed.

The above experiments were also compared with the Hampel method. As inExample 7 which duplicated the Hampel method, chlorine dioxide wasgenerated at a pH of 7.2 utilizing 0.040% of acetaldehyde (0.0091 molar)in buffer solution. The buffer solution was prepared by dissolving 34.5grams of sodium phosphate monobasic (NaH2PO4.H2O) in 500 ml of deionizedwater, adjusting the pH to 7.2 using a solution of sodium hydroxide andthen diluting to 1 liter with deionized water. Chlorine dioxideformation and the pH of the solution at room temperature in each ofthese experiments were measured at 2 minutes, 5 minutes and 10 minutesafter initial mixing.

The results of the above-described experiments for the control, themethod of Davidson and the instant invention are presented and comparedin Tables 5-8, below. The results of the Hampel experiment werepreviously presented in Tables 1-4 in Example 7, above and arere-presented in Tables 5-8 hereinbelow for purposes of comparison.Tables 5 and 7 evidence a large difference in the amount and rate offormation of chlorine dioxide using the present invention at an initialpH of about 3.5 and 4.5 compared with the methods of Davidson, thecontrol experiment or the Hampel Method. It is noted that the aldose anddiol disproportionation agents of Davidson were better than the controlexperiment in generating chlorine dioxide at pH 3.5 and 4.5, butsignificantly less efficient than the hydroxyl free aldehyde used in thepresent invention. For the Hampel method, the generation of chlorinedioxide ranged from slightly worse to slightly better than for thecontrol or Davidson experiment.

Tables 6 and 8 set forth the concentration of chlorite remaining insolution 10 minutes after initial mixing to form chlorine dioxide in thedifferent methods. The results evidence that the amount of chloriteremaining in solution after 10 minutes using the present invention issignificantly less than it is for the control experiment or theexperiments using the method of Davidson.

                                      TABLE 5                                     __________________________________________________________________________    PPM Level of Chlorine Dioxide Generated at pH 3.5                                                Davidson                                                   Time pH                                                                            Control                                                                            Present Invention                                                                      Mann.                                                                             Gluc.                                                                             Glyc.                                                                             Inos.                                                                            Hampel                                      __________________________________________________________________________    2 Min.                                                                             0.3 PPM                                                                            79.0 PPM 1.5 0.9 0.4 0.3                                                                              0.2                                         pH   3.5  3.6      3.5 3.5 3.5 3.5                                                                              7.2                                         5 Min.                                                                             0.4 PPM                                                                            96.0 PPM 2.2 1.4 0.4 0.3                                                                              0.6                                         pH   3.5  3.6      3.4 3.5 3.5 3.5                                                                              7.2                                         10 Min.                                                                            0.5 PPM                                                                            110 PPM  4.0 2.4 0.5 0.3                                                                              1.0                                         pH   3.5  3.7      3.4 3.5 3.4 3.5                                                                              7.2                                         __________________________________________________________________________     PPM = Parts Per Million                                                       Min. = Minutes                                                                N.D. = Not Detectable                                                         Mann. = Mannose (Aldose)                                                      Gluc. = Glucose (Aldose)                                                      Glyc. = Glycerin                                                              Inos. = Inositol (Cyclic Alcohol)                                        

                  TABLE 6                                                         ______________________________________                                        Percent Residual Levels of Sodium Chlorite (NaClO.sub.2)                      After 10 Minute Aging Period at pH 3.5                                        Experiment     pH     % NaClO.sub.2 Remaining                                 ______________________________________                                        Control        3.5    99.4%                                                   Present Invention                                                                            3.6    32                                                      Davidson                                                                      Mannose        3.4    about 97.8%                                             Glucose        3.5    about 98%                                               Glycerin       3.4    about 99.2%                                             Inositol       3.5    about 99.2%                                             Hampel         7.2    76.6%                                                   ______________________________________                                    

                                      TABLE 7                                     __________________________________________________________________________    PPM Level of Chlorine Dioxide Generated at pH 4.5                                                Davidson                                                   Time pH                                                                            Control                                                                            Present Invention                                                                      Mann.                                                                             Gluc.                                                                             Glyc.                                                                             Inos.                                                                            Hampel                                      __________________________________________________________________________    2 Min.                                                                             0.1 PPM                                                                            17.0 PPM 0.2 0.1 0.1 0.1                                                                              0.2                                         pH   4.5  4.6      4.4 4.4 4.4 4.4                                                                              7.2                                         5 Min.                                                                             0.1 PPM                                                                            24.0 PPM 0.2 0.2 0.1 0.1                                                                              0.6                                         pH   4.5  4.7      4.4 4.4 4.4 4.4                                                                              7.2                                         10 Min.                                                                            0.1 PPM                                                                            38.0 PPM 0.2 0.2 0.1 0.1                                                                              1.0                                         pH   4.5  4.7      4.3 4.4 4.4 4.5                                                                              7.2                                         __________________________________________________________________________     PPM = Parts Per Million                                                       Min. = Minutes                                                                N.D. = Not Detectable                                                         Mann. = Mannose (Aldose)                                                      Gluc. = Glucose (Aldose)                                                      Glyc. = Glycerin                                                              Inos. = Inositol (Cyclic Alcohol)                                        

                  TABLE 8                                                         ______________________________________                                        Percent Residual Levels of Sodium Chlorite (NaClO.sub.2)                      After 10 Minute Aging Period at pH 4.5                                        Experiment     pH     % NaClO.sub.2 Remaining                                 ______________________________________                                        Control        4.5    99.6%                                                   Present Invention                                                                            4.7    67                                                      Davidson                                                                      Mannose        4.3    about 98%                                               Glucose        4.4    about 98.4%                                             Glycerin       4.4    about 99.6%                                             Inositol       4.5    about 99.6%                                             Hampel         7.2    76.6%                                                   ______________________________________                                    

The results of the comparison experiments presented herein evidence theproduction of unexpectedly greater quantities of chlorine dioxide usingthe method of the present invention at a pH of about 3.5 to about 4.5compared to the prior art methods. While a combination of the teachingsof Hampel and Davidson suggest that the inclusion of a hydroxyl-freealdehyde disproportionation agent should result in less chlorine dioxidebeing formed compared with the same formulation which includes a vicinalhydroxyl-containing disproportionation agent, in fact the opposite istrue. In addition, the present invention is significantly more efficient(i.e., utilizes chlorite more efficiently) than are the prior artmethods. It is unexpected that the inclusion of a hydroxyl free aldehydein the method of the present invention would produce a such dramaticdifferences in the efficiency of the production of chlorine dioxide whencompared to the prior art methods described in Hampel and Davidson.

    ______________________________________                                        Ingredients        % w/w (Crude)                                              ______________________________________                                        Chlorite Part (A)                                                             Natrosol 250H NF   2.400                                                      Glycerin           4.000                                                      Myvaplex           1.000                                                      Dimethicone 193    1.000                                                      EDTA, Na.sub.4 (87%)                                                                             0.450                                                      Sodium laurylsulfate                                                                             0.020                                                      Sodium chlorite (80%)                                                                            2.000                                                      Propylene glycol   0.100                                                      Ethyl alcohol anhydrous                                                                          5.000                                                      Fragrance          0.020                                                      Water              q.s.                                                       Acid Part (B)                                                                 Natrosol 250H NF   2.400                                                      Potassium bisulfate anhydrous                                                                    0.710                                                      Propionaldehyde    0.070                                                      Glycerin           8.000                                                      Pluronic F68 NF    0.200                                                      Isopropyl alcohol anhydrous                                                                      6.000                                                      Myvaplex           1.000                                                      Dimethicone 193    1.000                                                      Fragrance          0.020                                                      Water              q.s.                                                       ______________________________________                                    

pH of the Chlorite Part=Falls Within the Range of About 10.0 to about11.5

pH of Acid Part=Range of about 2.10 to about 2.25, preferably about2.20.

pH of Chlorite Part (A)+Acid Part (B) at 1:1 mixing ratio=4.0

The levels of chlorine dioxide generated after 2 minutes aging period isabout 60 ppm. Due to opacity of the mixture, chlorine dioxide levelswere measured by amperometric method using a platinum redox electrode atroom temperature.

The ingredients which are included in the formulation produce theconsistency of a hand lotion having disinfecting qualities.

Natrosol 250H is a NF grade of hydroxyethylcellulose and is the gellingagent used in this example

Myvaplex is a brand name glyceryl monostearate and is used as a skinconditioner and softener.

Dimethicone 193 is a cosmetic grade of dimethylsiloxane silicon polymerand is included as a lubricant, film-former and as an emulsifier.

Glycerin and propylene glycol are widely used as humectants in cosmeticpreparations.

Sodium laurylsulfate is used in cosmetics as a surface active agent(surfactant) and a cleaning agent.

Ethyl alcohol is used as a solvent for Myvaplex.

EDTA, Na₄ is included as an alkali.

Pluronic F68 NF is a polyoxypropylene (POP)-polyoxyethylene (POE) blockcopolymer and is included as a surfactant.

Isopropyl alcohol is included as a solvent and an emulsifier.

    ______________________________________                                        Ingredients        % w/w (Crude)                                              ______________________________________                                        Chlorite Part (A)                                                             Natrosol 250H NF   2.800                                                      Glycerin           0.100                                                      EDTA, Na.sub.4 (87%)                                                                             0.400                                                      Sodium chlorite (80%)                                                                            2.000                                                      Isopropyl alcohol anhydrous                                                                      5.000                                                      Fragrance          0.020                                                      Water              q.s.                                                       Acid Part (B)                                                                 Natrosol 250H NF   2.400                                                      Potassium bisulfate anhydrous                                                                    0.710                                                      Propionaldehyde    0.070                                                      Glycerin           8.000                                                      Pluronic F68 NF    0.400                                                      Isopropyl alcohol anhydrous                                                                      2.000                                                      Fragrance          0.020                                                      Water              q.s.                                                       ______________________________________                                    

pH of the Chlorite Part=Falls Within the Range of About 10.0 to about11.5

pH of Acid Part=Range of about 2.10 to about 2.25, preferably about2.20.

pH of Chlorite Part (A)+Acid Part (B) at 1:1 mixing ratio=range of 3.6to 4.0, preferably 3.80.

The levels of chlorine dioxide generated after 2 minutes aging period isabout 50 ppm. Due to opacity of the mixture, chlorine dioxide levelswere measured by amperometric method using a platinum redox electrode atroom temperature.

Example 12 Comparison of the Present Gel Composition at a pH of about4.5 With Prior Art Composition of Davidson

The present invention which also relates to gel formulations for topicaldelivery to a human or animal patient, employing a vicinal hydroxyl freealdehyde in combination with a salt of chlorite and an acid at aninitial pH of about 4.5 was compared with the method and compositionsdescribed in U.S. patent application No. 4,986,990 ("Davidson"). Thisexample was performed merely to assure the inventor that the generaldiscovery of the rate of formation of chlorine dioxide utilizing theclaimed inventive compositions was readily translated to formulationswhich contained amounts of a gelling agent effective to gel thecompositions.

Chlorine dioxide was generated using the present invention(propionaldehyde at a concentration of 0.0122M was used as thedisproportionation agent for the present invention) and theabove-referenced prior art method of Davidson (D-mannose was used as thedisproportionation agent in the Davidson composition at a concentrationof 0.0122M) in the following experiments, which were performed at roomtemperature under essentially identical conditions (initial sodiumchlorite and disproportionation agent concentration). The initial pH wasconstant at about 4.5. Chlorine dioxide was generated by mixing equalamounts of parts A and B. Levels of chlorine dioxide were determined foreach experiment by the following method.

For the purpose of accurate measurements, after parts A and B weremixed, after the indicated time periods, known quantities of the gelmixtures were placed in known volumes of deionized water and allowed todissolve. The resulting aqueous mixtures were then evaluatedspectrophotometrically for their chlorine dioxide contents, using awavelength of 360 nm. Sodium chlorite levels were determined byiodometric titrations using 0.1N thiosulfate reagent. A separatetitration was carried out, as a control, for quantification of sodiumchlorite at time zero, which resulted in 0.839 percent sodium chlorite.

    ______________________________________                                                          % w/w                                                       ______________________________________                                        For the present invention:                                                    Part (A)                                                                      Natrosol 250H NF    2.800                                                     Sodium chlorite (80%)                                                                             2.098                                                     EDTA, Na.sub.4 (87%)                                                                              0.400                                                     Isopropyl alcohol anhyd.                                                                          5.000                                                     Water               89.702                                                    Part (B)                                                                      Natrosol 250H NF    2.400                                                     Potassium bisulfate anhyd.                                                                        0.680                                                     Propionaldehyde     0.071                                                     Water               96.849                                                    For the Davidson Reference:                                                   Part (A) as above                                                             Part (B)                                                                      Natrosol 250H NF    2.400                                                     Potassium bisulfate anhyd.                                                                        0.680                                                     D-Mannose           0.220                                                     Water               96.700                                                    ______________________________________                                    

Part (A) as set forth above was used to produce compositions accordingto the present invention and to replicate the composition of Davidson.The results of the experiment appear in Tables 9 and 10, below.

                  TABLE 9                                                         ______________________________________                                        Chlorine Dioxide Generation                                                                 PPM Chlorine Dioxide                                                          Generated                                                                     After 2 Min.                                                                           After 10 Min.                                          ______________________________________                                        Present Invention                                                                             27         35                                                 Davidson Composition                                                                          ≦1   2                                                 ______________________________________                                    

                  TABLE 10                                                        ______________________________________                                        Percent Levels of Sodium Chlorite Detected                                                  After 2 Min.                                                                           After 10 Min.                                          ______________________________________                                        Present Invention                                                                             0.8310     0.7900                                             Davidson Composition                                                                          0.8386     0.8384                                             ______________________________________                                    

The results of this experiment indicate that the present inventionproduces unexpectedly greater quantities of chlorine dioxide compared tothe Davidson compositions as was shown in the aqueous system. It isclear that the unexpected result produced by the combination of hydroxylfree aldehydes and sodium chlorite at an acidic pH in an aqueous systemis clearly translatable to an aqueous system which includes a gellingagent. The modification in rheology of gel compositions according to thepresent invention did not negate the enhanced generation of chlorinedioxide in compositions according to the present invention compared tothe prior art methods of generating chlorine dioxide.

This invention has been described in terms of specific embodiments setforth in detail herein, but it should be understood that these are byway of illustration and the invention is not necesarily limited thereto.Modifications and variations will be apparent from the disclosure andmay be resorted to without departing from the spirit of the inventionsthose of skill in the art will readily understand. Accordingly, suchvariations and modifications are considered to be within the purview andscope of the invention and the following claims.

I claim:
 1. A method of producing chlorine dioxide comprising:combiningin a first aqueous solution an aqueous soluble chlorite salt, an aqueoussoluble acid and an aqueous soluble hydroxyl free aldehydedisproportionation agent, said chlorite salt, said acid and saidaldehyde disproportionation agent being included in said first solutionin concentrations effective in combination to produce chlorine dioxidein a concentration of at least about 5 parts per million after a periodof about ten minutes, said first solution having an initial pH of about5.0 or less, said first solution producing at least twice theconcentration of chlorine dioxide after said period compared to a secondaqueous solution identical to said first solution except that an aldosedisproportionation agent is substituted for said aldehydedisproportionation agent in said second solution at the same molarconcentration said aldehyde disproportionation agent is included in saidfirst solution.
 2. The method according to claim 1 wherein said acid isselected from the group consisting of aqueous soluble bisulfate salts,sulfamic acid, maleic acid, phosphoric acid, ethylenediaminetetraaceticacid, monosodium ethylenediaminetetraacetic acid and mixtures thereof.3. The method according to claim 2 wherein said chlorite salt isselected from sodium chlorite and potassium chlorite.
 4. The methodaccording to claim 1 wherein said aldehyde is selected from the groupconsisting of acetaldehyde, benzaldehyde, propionaldehyde,glutaraldehyde and 2-furfural.
 5. The method according to claim 1wherein said aldehyde is selected from the group consisting ofglutaraldehyde, acetaldehyde, benzaldehyde and propionaldehyde.
 6. Themethod according to claim 1 wherein said first aqueous solution has aninitial pH of about 3.0 to about 4.5 and further includes an amount of agelling agent effective to gel said solution.
 7. The method according toclaim 6 wherein said first aqueous solution further includes at leastone additive selected from the group consisting of surfactants,emulsifiers, emollients, wound healing agents, lubricants, film-formers,diluents, fillers, humectants and penetration enhancers.
 8. The methodaccording to claim 1 wherein said first aqueous solution has an initialpH of about 3.5 to 4.5.
 9. The method according to claim 1 wherein saidchlorine dioxide is produced in said first solution after said period ina concentration of at least four times the concentration of chlorinedioxide produced in said second solution.
 10. A method of producingchlorine dioxide comprising:combining in a first aqueous solution anaqueous soluble chlorite salt, an acid selected from the groupconsisting of an aqueous soluble bisulfate salt, sulfamic acid, maleicacid, phosphoric acid, ethylenediaminetetraacetic acid, monosodiumethylenediaminetetracetic acid and mixtures thereof and an aldehydedisproportionation agent selected from the group consisting ofacetaldehyde, propionaldehyde, glutaraldehyde, 2-furfural, and mixturesthereof, said chlorite salt, said acid and said disproportionation agentbeing included in said first solution in concentrations effective incombination to produce chlorine dioxide in a concentration of at leastabout 5 parts per million after a period of about ten minutes, saidfirst solution having an initial pH of about 5.0 or less, said firstsolution producing at least twice the concentration of chlorine dioxideafter said period compared to a second aqueous solution identical tosaid first solution except that an aldose disproportionation agent issubstituted for said aldehyde disproportionation agent in said secondsolution at the same molar concentration said aldehydedisproportionation agent is included in said first solution.
 11. Themethod according to claim 10 wherein said acid is an aqueous solublebisulfate salt is selected from the group consisting of sodium bisulfateand potassium bisulfate.
 12. The method according to claim 10 whereinsaid acid is phosphoric acid.
 13. The method according to claim 10wherein said aldehyde is selected from the group consisting ofacetaldehyde, benzaldehyde, propionaldehyde and glutaraldehyde.
 14. Themethod according to claim 10 wherein said chlorite salt is selected fromthe group consisting of potassium chlorite and sodium chlorite.
 15. Themethod according to claim 10 wherein said first aqueous solution has aninitial pH of about 3.0 to about 4.5 and further includes an amount of agelling agent effective to gel said solution.
 16. The method accordingto claim 15 wherein said aqueous solution further includes at least oneadditive selected from the group consisting of surfactants, emulsifiers,emollients, wound healing agents, lubricants, film-formers, diluents,fillers, humectants and penetration enhancers.
 17. The method accordingto claim 10 wherein said aqueous solution has an initial pH of about 3.5to 4.5.
 18. The method according to claim 10 wherein said chlorinedioxide is produced in said first solution after said period in aconcentration of at least four times the concentration of chlorinedioxide produced in said second solution.
 19. A method of producingchlorine dioxide comprising combining an amount of an aqueous solublechlorite salt in solution with an amount of an acid selected from thegroup consisting of an aqueous soluble bisulfate salt, sulfamic acid,maleic acid, phosphoric acid, ethylenediaminetetraacetic acid,monosodium ethylenediaminetetracetic acid and mixtures thereof incombination with an amount of a hydroxyl-free aldehydedisproportionation agent selected from the group consisting ofglutaraldehyde, propionaldehyde, acetaldehyde, benzaldehyde and2-furfural effective to produce chlorine dioxide in a concentration ofat least about 5 parts per million, said solution after combining saidchlorite salt, said acid and said disproportionation agent having aninitial pH of less than about 4.5, said disproportionation agentsubstantially increasing the rate of formation of chlorine dioxide andminimizing residual chlorite in said solution in comparison to methodswhich otherwise the same except utilizing aldose disproportionationagents rather than hydroxyl-free aldehyde disproportionation agents. 20.The method according to claim 19 wherein said initial pH ranges fromabout 3.5 to about 4.5.
 21. The method according to claim 19 whereinsaid acid is an aqueous soluble salt of bisulfate selected from thegroup consisting of sodium bisulfate and potassium bisulfate.
 22. Themethod according to claim 19 wherein said acid is phosphoric acid. 23.The method according to claim 19 wherein said acid is added in an amounteffective to produce an initial pH of said solution of less than about2.5.
 24. The method according to claim 6 wherein said gelling agent isselected from the group consisting of hydroxymethyl cellulose,hydroxyethyl cellulose and hydroxypropyl cellulose.
 25. The methodaccording to claim 15 wherein said gelling agent is selected from thegroup consisting of hydroxymethyl cellulose, hydroxyethyl cellulose andhydroxypropyl cellulose.